KR100650207B1 - Glutaryl 7-amino-3-vinyl-cephalosporanic acid derivatives and process for preparing it - Google Patents

Glutaryl 7-amino-3-vinyl-cephalosporanic acid derivatives and process for preparing it Download PDF

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KR100650207B1
KR100650207B1 KR1020050069223A KR20050069223A KR100650207B1 KR 100650207 B1 KR100650207 B1 KR 100650207B1 KR 1020050069223 A KR1020050069223 A KR 1020050069223A KR 20050069223 A KR20050069223 A KR 20050069223A KR 100650207 B1 KR100650207 B1 KR 100650207B1
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강태원
전관준
손회주
박용규
최원규
장관영
진경용
방성훈
이광섭
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D501/00—Heterocyclic compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
    • C07D501/14—Compounds having a nitrogen atom directly attached in position 7
    • C07D501/16—Compounds having a nitrogen atom directly attached in position 7 with a double bond between positions 2 and 3
    • C07D501/20—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids
    • C07D501/22—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids with radicals containing only hydrogen and carbon atoms, attached in position 3
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
    • A61K31/542—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/545—Compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins, cefaclor, or cephalexine

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Abstract

A novel glutaryl 7-amino-3-vinyl-cephalosporanic acid derivative is provided to be used for synthesizing cephalosporin antibiotics. And a method for economically preparing thereof from glutaryl 7-aminocephalosporanic acid is provided. The glutaryl 7-amino-3-vinyl-cephalosporanic acid derivative is represented by the formula(1), where R1 is H, alkali metal or C1-10 alkyl-substituted silyl, each R2 and R3 is independently H, C1-6 alkyl, phenyl, thiazole, or C1-6 alkyl substituted thiazole.

Description

글루타릴 7-아미노-3-비닐-세팔로스포란산 유도체와 이의 제조방법{Glutaryl 7-amino-3-vinyl-cephalosporanic acid derivatives and process for preparing it}Glutaryl 7-amino-3-vinyl-cephalosporanic acid derivatives and process for preparing it}

본 발명은 세팔로스포린계 항생제 합성에 사용되어지는 신규 구조의 하기 화학식 1로 표시되는 글루타릴 7-아미노-3-비닐-세팔로스포란산 유도체와 이의 제조방법에 관한 것이다.The present invention relates to a glutaryl 7-amino-3-vinyl-cephalosporanic acid derivative represented by the following formula (1) of a novel structure used for synthesizing cephalosporin-based antibiotics and a method for preparing the same.

[화학식 1][Formula 1]

Figure 112005041757564-pat00002
Figure 112005041757564-pat00002

상기 화학식 1에서, R1은 수소원자, 알카리금속원자, 또는 C1~C10의 알킬치환된 실릴기를 나타내고; R2와 R3는 서로 같거나 다른 것으로서 수소원자, C1~C6의 알킬기, 페닐기, 티아졸기, 또는 C1~C6의 알킬 치환된 티아졸기를 나타낸다.In Formula 1, R 1 represents a hydrogen atom, an alkali metal atom, or an alkyl substituted silyl group of C 1 to C 10 ; R 2 and R 3, which may be the same or different, represent a hydrogen atom, an alkyl group of C 1 to C 6 , a phenyl group, a thiazole group, or an alkyl substituted thiazole group of C 1 to C 6 .

일반적으로 세팔로스포린계 화합물은 7-아미노세팔로스포란산의 C-7 위치의 아미노기를 아실화하거나, 또는 C-3 위치에 아세톡시기를 친핵성 치환반응에 의해 도입하는 방법으로 합성되어지고 있다. 그러나, 7-아미노세팔로스포란산은 비경제적으로 산업화시 어렵기 때문에 보다 저렴한 출발물질이 필요하다.Generally, cephalosporin-based compounds are synthesized by acylating the amino group at the C-7 position of 7-aminocephalosporane acid or introducing the acetoxy group at the C-3 position by nucleophilic substitution. ought. However, since 7-aminocephalosporranic acid is uneconomically difficult to industrialize, a cheaper starting material is needed.

세팔로스포린계 화합물로서 3-알케닐 세펨화합물(세픽심, 세프디니르, 세프디토렌, 세프로질 등)을 합성하는데 있어서는, 7-아미노세팔로스포란산 그 자체로 사용될 수 없고 다단계의 화학반응을 거쳐서만이 합성할 수 있다. 즉, 7-아미노세팔로스포란산의 C-7 위치의 아미노기를 아실화 또는 이동염기(Schiff's base)로 변화하거나, 또는 C-4 위치의 카르복실기를 에스테르화 하는 등의 복잡한 일련의 화학적 반응을 거쳐야만 한다. 또, 보호화 반응 후, 할로겐화반응, 포스포늄염을 거쳐 각종 알데히드와의 비티히 반응으로 C-3 위치에 비닐기를 도입하고, 두 개의 보호기를 다시 각각 탈보호화 시키는 복잡한 공정을 수행하여야 비로서 원하는 3-알케닐 세펨화합물을 합성할 수가 있다(미국특허 4,585,860, 미국특허 4,520,022). 상기한 방법은 보호반응과 탈보호반응을 수행하고 있어 제조단계가 매우 복잡하며, 불안정한 중간체로 생성으로 인해 비실용적이고, 수율도 매우 저조하므로 대량 생산공정에 적용하기에는 어려움이 있다. In synthesizing 3-alkenyl cefem compounds (cepicsim, ceftinir, ceftitorene, ceprozil, etc.) as cephalosporin-based compounds, 7-aminocephalosporranic acid cannot be used on its own and is multistage. It can only be synthesized by chemical reaction. That is, a complex series of chemical reactions such as changing the amino group at the C-7 position of 7-aminocephalosporranic acid to an acylation or a Schiff's base, or esterifying a carboxyl group at the C-4 position are performed. It must go through. In addition, after the protection reaction, a complex process of introducing a vinyl group at the C-3 position through a halogenation reaction, a phosphonium salt and a Wittich reaction with various aldehydes, and then deprotecting the two protecting groups, respectively, must be carried out. 3-alkenyl cefem compounds can be synthesized (US Pat. No. 4,585,860, US Pat. No. 4,520,022). The above-mentioned method is very complicated to produce a protective reaction and deprotection reaction, it is impractical due to the production of unstable intermediate, and the yield is very low, it is difficult to apply to the mass production process.

한편, 유럽특허 제503453호에서는 보호기로 실릴기를 이용함으로써 반응단계를 간소하였다. 하지만 이 방법에서도 실릴화시 반응시간이 매우 길어 공정단가가 높아지고, C-7 위치의 아미노기의 탈실릴화로 인해 미반응 및 부반응 가능성 이 커 수율에 영향을 주며, 생성되는 화합물들의 유기용매에 대한 용해도가 매우 낮기 때문에 추출대신 수용액에서 즈비터이온(zwitter ion)으로 석출해야만 하는 어려움이 있어 석출 시 수용액상에 남아있는 화합물의 손실이 불가피하였다.On the other hand, European Patent No. 503453 uses a silyl group as a protecting group to simplify the reaction step. However, in this method, too, the reaction time is very long during silylation, which increases the process cost, and desilylation of the amino group at the C-7 position increases the possibility of unreacted and side reactions, which affects the yield and the solubility of the resulting compounds in the organic solvent. Because of the very low is difficult to precipitate as zwitter ion (zwitter ion) in the aqueous solution instead of extraction, the loss of the compound remaining in the aqueous solution during precipitation is inevitable.

이에 본 발명의 발명자들은 이러한 단점을 최소화하여 산업적으로 생산 가능한 3-알케닐 세펨계 화합물을 합성하고자 연구 노력하였다Accordingly, the inventors of the present invention have tried to synthesize 3-alkenyl cefem compounds that can be industrially produced by minimizing these disadvantages.

그 결과, 글루타릴 7-아미노세팔로스포란산 유도체로서 국제특허공개 WO 95/35020호에 공지되어 있는 하기 화학식 2로 표시되는 화합물을 출발물질로 사용하여, 경제적인 방법으로 하기 화학식 1로 표시되는 신규 구조의 글루타릴 7-아미노-3-비닐-세팔로스포란산 유도체를 합성함으로써 본 발명을 완성하게 되었다. As a result, using a compound represented by the following formula (2), known in WO 95/35020 as a starting material, as a glutaryl 7-aminocephalosporanic acid derivative as a starting material, The present invention has been completed by synthesizing glutaryl 7-amino-3-vinyl-cephalosporan acid derivatives of the novel structure shown.

Figure 112005041757564-pat00003
Figure 112005041757564-pat00003

따라서, 본 발명은 상기 화학식 1로 표시되는 글루타릴 7-아미노-3-비닐-세팔로스포란산 유도체를 제공하는데 그 목적이 있다.Accordingly, an object of the present invention is to provide a glutaryl 7-amino-3-vinyl-cephalosporanic acid derivative represented by the formula (1).

또한, 본 발명은 상기 화학식 2로 표시되는 화합물을 출발물질로 사용하여 경제적인 합성방법으로 상기 화학식 1로 표시되는 글루타릴 7-아미노-3-비닐-세팔로스포란산 유도체를 제조하는 방법을 제공하는데 다른 목적이 있다.In addition, the present invention is a method for preparing a glutaryl 7-amino-3-vinyl-cephalosporanic acid derivative represented by the formula (1) by an economical synthesis method using the compound represented by the formula (2) as a starting material There is another purpose to provide.

또한, 본 발명은 상기한 제조과정을 수행하는 중에 생성되는 신규 중간체 화합물을 제공하는데도 또 다른 목적이 있다.In addition, the present invention has another object to provide a novel intermediate compound produced during the above-described preparation process.

본 발명은 세팔로스포린계 항생제 합성에 사용되어지는 신규 구조의 하기 화학식 1로 표시되는 글루타릴 7-아미노-3-비닐-세팔로스포란산 유도체를 그 특징으로 한다.The present invention is characterized by a glutaryl 7-amino-3-vinyl-cephalosporic acid derivative represented by the following formula (1) of a novel structure used for synthesizing cephalosporin-based antibiotics.

[화학식 1][Formula 1]

Figure 112005041757564-pat00004
Figure 112005041757564-pat00004

상기 화학식 1에서, R1은 수소원자, 알카리금속원자, 또는 C1~C10의 알킬치환된 실릴기를 나타내고; R2와 R3는 서로 같거나 다른 것으로서 수소원자, C1~C6의 알킬기, 페닐기, 티아졸기, 또는 C1~C6의 알킬 치환된 티아졸기를 나타낸다.In Formula 1, R 1 represents a hydrogen atom, an alkali metal atom, or an alkyl substituted silyl group of C 1 to C 10 ; R 2 and R 3, which may be the same or different, represent a hydrogen atom, an alkyl group of C 1 to C 6 , a phenyl group, a thiazole group, or an alkyl substituted thiazole group of C 1 to C 6 .

본 발명에 따른 상기 화학식 1로 표시되는 화합물에 있어, 구체적으로 R1은 수소원자; 칼륨(K), 나트륨(Na), 리튬(Li)을 포함하는 알카리금속원자; 또는 트리메틸실릴, 트리에틸실릴, tert-부틸디메틸실릴, 트릴이소프로필실릴을 포함하는 알킬치환된 실릴기이고, R2와 R3는 서로 같거나 다른 것으로서 수소원자; 메틸, 에틸, n-프로필, 이소부틸, tert-부틸 등의 직쇄 또는 분쇄상의 알킬기; 페닐기; 티아졸 기; 또는 4-메틸 티아졸을 포함하는 알킬 치환된 티아졸기일 수 있다.In the compound represented by Chemical Formula 1 according to the present invention, specifically R 1 is a hydrogen atom; Alkali metal atoms including potassium (K), sodium (Na), and lithium (Li); Or an alkyl-substituted silyl group including trimethylsilyl, triethylsilyl, tert-butyldimethylsilyl, trilyisopropylsilyl, and R 2 and R 3 are the same as or different from each other and are hydrogen atoms; Linear or pulverized alkyl groups such as methyl, ethyl, n-propyl, isobutyl and tert-butyl; Phenyl group; Thiazole groups; Or an alkyl substituted thiazole group including 4-methyl thiazole.

상기 화학식 1로 표시되는 화합물에 있어, 바람직하기로는 R1은 수소원자, 나트륨원자, 또는 트리메틸실릴기이고, R2와 R3는 서로 같거나 다른 것으로서 수소원자; 메틸, 에틸, n-프로필, 이소부틸, tert-부틸 등의 직쇄 또는 분쇄상의 알킬기; 티아졸기; 또는 4-메틸 티아졸 인 화합물의 경우이다.In the compound represented by Formula 1, preferably, R 1 is a hydrogen atom, a sodium atom, or a trimethylsilyl group, and R 2 and R 3 are the same as or different from each other; Linear or pulverized alkyl groups such as methyl, ethyl, n-propyl, isobutyl and tert-butyl; Thiazole group; Or 4-methyl thiazole phosphorus compound.

상기 화학식 1로 표시되는 화합물에 있어, 특히 바람직하기로는 하기 화학식 1a, 1b 또는 1c로 표시되는 화합물의 경우이다.In the compound represented by the above formula (1), particularly preferably, the compound represented by the following formula (1a), (1b) or (1c).

Figure 112005041757564-pat00005
,
Figure 112005041757564-pat00006
,
Figure 112005041757564-pat00007
Figure 112005041757564-pat00005
,
Figure 112005041757564-pat00006
,
Figure 112005041757564-pat00007

한편, 본 발명은 상기 화학식 2로 표시되는 화합물을 출발물질로 사용하여 상기 화학식 1로 표시되는 글루타릴 7-아미노-3-비닐-세팔로스포란산 유도체를 제조하는 방법을 포함한다.On the other hand, the present invention includes a method for preparing glutaryl 7-amino-3-vinyl-cephalosporanic acid derivative represented by Formula 1 using the compound represented by Formula 2 as a starting material.

본 발명이 출발물질로 사용하는 상기 화학식 2로 표시되는 화합물은 국제특허공개 WO95/35020호에 공지된 화합물로서 공지방법으로 쉽게 합성하여 사용할 수 있다. 예를 들면, 글루타릴 7-아미노세팔로스포란산을 일반적인 실릴화제로 2시간 정도 실릴화한 후에, 할로겐화제로 반응시켜 C-3 위치가 치환된 상기 화학식 2로 표시되는 화합물을 합성할 수가 있다. 상기한 실릴화제는 유럽특허 제43630호에 기재된 것으로, 헥사메틸디실라잔, 헥사메틸디실란, N-0-비스트리메틸실릴아세트아미드, 비스실릴우레아 등이 바람직하게 사용될 수 있다. 할로겐화제로는 일반적으로 요오도트리메틸실란과 같은 요오드화제가 바람직하게 사용될 수 있다. The compound represented by Chemical Formula 2 used as the starting material of the present invention can be easily synthesized by a known method as a compound known from WO 95/35020. For example, after silylating glutaryl 7-aminocephalosporranic acid with a common silylating agent for about 2 hours, the compound represented by Chemical Formula 2 having the C-3 position substituted by the halogenating agent can be synthesized. have. The above silylating agent is described in European Patent No. 43630, and hexamethyldisilazane, hexamethyldisilane, N-0-bistrimethylsilylacetamide, bissilylurea and the like can be preferably used. In general, as the halogenating agent, an iodinating agent such as iodotrimethylsilane may be preferably used.

본 발명에 따른 제조방법은, 하기 반응식 1에 나타낸 바와 같이 하기 화학식 2로 표시되는 화합물을 출발물질로 사용하여 포스포릴화 반응, 알칼리 금속의 염기 존재하에서 반응 및 알데하이드 화합물과의 비티히 반응을 포함하여 이루어진다.The preparation method according to the present invention includes a phosphorylation reaction, a reaction in the presence of an alkali metal base, and a Wittich reaction with an aldehyde compound using a compound represented by the following Chemical Formula 2 as a starting material, as shown in Scheme 1 below. It is done by

Figure 112005041757564-pat00008
Figure 112005041757564-pat00008

상기 반응식 1에서, R1, R2, 및 R3은 각각 상기 화학식 1에서 정의한 바와 같고; X는 할로겐원자를 나타내고; A는 P(R4)3I, 또는 P(O)(OR4)2를 나타내고; B+는 P+(R4)3, 또는 P(O)(OR4)2Y+를 나타내고; R4는 C1~C6의 알킬기, 페닐기, 또는 C1~C6의 알콕시 치환된 페닐기를 나타낸다.In Reaction Scheme 1, R 1 , R 2 , and R 3 are each as defined in Formula 1; X represents a halogen atom; A represents P (R 4 ) 3 I, or P (O) (OR 4 ) 2 ; B + represents P + (R 4 ) 3 , or P (O) (OR 4 ) 2 Y + ; R 4 represents a C 1 to C 6 alkyl group, a phenyl group, or a C 1 to C 6 alkoxy substituted phenyl group.

상기 반응식 1에 따른 본 발명의 제조방법은 각 단계별로 생성되는 중간체 화합물을 분리 정제하면서 진행할 수도 있겠으나, 필요에 따라 중간체 분리과정 없이 연속적 공정으로 수행하여도 본 발명이 목적하는 효과는 충분히 달성될 수 있으며, 공업적인 생산방법에서는 연속공정이 보다 경제성이 있어 바람직하다할 수 있다.The preparation method of the present invention according to Scheme 1 may proceed while separating and purifying the intermediate compound produced in each step, but the desired effect of the present invention can be sufficiently achieved even if performed in a continuous process without intermediate separation process if necessary. In an industrial production method, a continuous process may be preferable since it is more economical.

다음에서는 본 발명의 제조방법을 설명함에 있어, 각 단계별로 구분하여 상세히 설명하도록 하겠다.In the following description of the manufacturing method of the present invention, it will be described in detail by dividing each step.

제 1단계는, 상기 화학식 2로 표시되는 화합물을 포스포릴화 반응하여 상기 화학식 3으로 표시되는 화합물을 합성하는 과정이다.The first step is a process of synthesizing the compound represented by Chemical Formula 3 by phosphorylation of the compound represented by Chemical Formula 2.

상기 포스포릴화 반응에는 포스포릴화제로서 트리페닐 포스핀, 트리-p-메톡시페닐 포스핀, 트리메틸 포스핀, 트리에틸 포스핀, 트리페닐 포스페이트, 트리에틸 포스페이트 등이 사용될 수 있으며, 특히 바람직하기로는 트리페닐 포스핀을 사용하는 것이다. 포스포릴화 반응온도는 -10 ℃ 내지 상온 범위를 유지하도록 하며, 보다 바람직하게는 0 ℃ 내지 10 ℃를 유지하는 것이다.In the phosphorylation reaction, triphenyl phosphine, tri-p-methoxyphenyl phosphine, trimethyl phosphine, triethyl phosphine, triphenyl phosphate, triethyl phosphate, etc. may be used as the phosphorylating agent. Is to use triphenyl phosphine. The phosphorylation reaction temperature is to maintain the range from -10 ℃ to room temperature, more preferably to maintain 0 ℃ to 10 ℃.

제 2단계는, 상기 화학식 3으로 표시되는 화합물을 알칼리 금속의 염기존재 하에서 반응시켜 상기 화학식 4로 표시되는 화합물을 합성하는 과정이다.The second step is a process of synthesizing the compound represented by Chemical Formula 4 by reacting the compound represented by Chemical Formula 3 in the presence of an alkali metal base.

상기 알카리 금속염기라 함은 칼륨(K), 나트륨(Na), 리튬(Li) 등의 알칼리금속과 결합된 염기를 말하며, 예컨대 강염기로는 헥사메틸디실라잔, 이소프로필아민, 히드라드, 부틸기와 결합된 알카리금속의 염이 포함될 수 있고, 약염기로는 아세토아세트산, 벤조산, 피발산, 아세트산, 말로산과 그의 알카리 금속염이 포함될 수 있다. 상기 알칼리 금속의 염기존재 하에서의 반응온도는 -40 ℃ 내지 40 ℃ 범위를 유지하도록 하며, 보다 바람직하게는 -20 ℃ 내지 25 ℃ 범위를 유지하도록 하며, 특히 바람직하게는 -10 ℃ 정도를 유지하는 것이다.The alkali metal base refers to a base combined with an alkali metal such as potassium (K), sodium (Na), or lithium (Li). For example, the strong base includes hexamethyldisilazane, isopropylamine, hydrad, and butyl group. Salts of the bound alkali metals may be included, and weak bases may include acetoacetic acid, benzoic acid, pivalic acid, acetic acid, malo acid and alkali metal salts thereof. The reaction temperature in the presence of the base of the alkali metal is to maintain the range of -40 ℃ to 40 ℃, more preferably to maintain the range of -20 ℃ to 25 ℃, and particularly preferably to maintain about -10 ℃ .

제 3단계는, 상기 화학식 4로 표시되는 화합물을 알데히드 화합물과 비티히 반응시켜 상기 화학식 1로 표시되는 화합물을 합성하는 과정이다.The third step is a process of synthesizing the compound represented by Chemical Formula 1 by reacting the compound represented by Chemical Formula 4 with an aldehyde compound.

알데히드 화합물로서는 예컨대 포름알데히드, 아세트알데히드, 클로로아세트알데히드, 이소부틸알데히드 등의 직쇄 또는 분기상 저급 알데히드, 벤즈알데히드, 4-메틸-티아졸-5-카브알데히드, 톨릴알데히드 등의 아릴알데히드 등을 사용될 수 있다. 특히 포름알데히드는 세픽심, 세프디니르 등을 합성하는데 필요한 핵심 치환체이며, 아세트알데히드는 세프프로질 합성하는데 필요한 핵심 치환체이며, 4-메틸-티아졸-5-카브알데히드는 세프디토렌을 합성하는데 필요한 핵심 치환체이다. 상기 알데히드 화합물과의 반응온도는 -30 ℃ 내지 30 ℃ 범위를 유지하도록 하며, 보다 바람직하게는 -10 ℃ 내지 0 ℃ 범위를 유지하도록 하는 것이다.As the aldehyde compound, for example, linear or branched lower aldehydes such as formaldehyde, acetaldehyde, chloroacetaldehyde, isobutyl aldehyde, benzaldehyde, 4-methyl-thiazole-5-carbaldehyde, tolylaldehyde and the like can be used. have. In particular, formaldehyde is a key substituent necessary for synthesizing Seppicsim, Cefdinir, and the like, acetaldehyde is a key substituent required for Cefprozil synthesis, and 4-methyl-thiazole-5-carbaldehyde is used for synthesizing ceftitorene. Are the key substituents required. The reaction temperature with the aldehyde compound is to maintain the range of -30 ℃ to 30 ℃, more preferably to maintain the range of -10 ℃ to 0 ℃.

또한, 상기한 알데히드 화합물과의 반응을 수행함에 있어 필요에 따라 실릴화합물을 첨가할 수도 있는 바, 실릴화합물이 첨가된 상태에서 알데히드 화합물과의 반응을 수행하게 되면 보다 원활하게 반응이 진행되는 효과를 얻을 수 있다. 알데히드 화합물과의 반응에 사용되는 실릴화합물은 실릴기 함유 화합물은 모두 적용이 가능하며, 구체적으로 헥사메틸디실라잔, 헥사메틸디실란, N-0-비스트리메틸실릴아세트아미드, 비스실릴우레아 등이 포함될 수 있다. In addition, the silyl compound may be added as needed in the reaction with the aldehyde compound. When the reaction with the aldehyde compound is performed in the state where the silyl compound is added, the reaction proceeds more smoothly. You can get it. As the silyl compound used for the reaction with the aldehyde compound, all silyl group-containing compounds can be applied. May be included.

상기한 각 제조단계에서는 반응용매로서 테트라히드로퓨란, 디에틸에테르, 에틸렌글리콜디에틸에테르, 디메틸술폭시드, tert-부틸에테르 등의 불활성 에테르계와 디메틸포름아미드, 디에틸아세트아미드, 1-메틸-2-피롤리디논 등의 불활성 아미드계, 아세토니트릴과 같은 니트릴계, 클로로포름, 디클로로에탄, 디클로로메탄 등의 할로겐화 탄화수소류 등 중에서 선택된 단독 용매 또는 혼합용매를 사용할 수 있다. 특히 바람직한 용매로서는 불활성 용매로서 디메틸포름아미드, 디메틸포름아미드, 1-메틸-2-피롤리디논, 디메틸술폭시드를 주용매로 하는 혼합용매를 사용하는 것이다.In each of the above production steps, inert ethers such as tetrahydrofuran, diethyl ether, ethylene glycol diethyl ether, dimethyl sulfoxide, tert-butyl ether, dimethylformamide, diethylacetamide and 1-methyl- as reaction solvents. A single solvent or a mixed solvent selected from inert amides such as 2-pyrrolidinone, nitrile such as acetonitrile, and halogenated hydrocarbons such as chloroform, dichloroethane and dichloromethane can be used. As a particularly preferable solvent, a mixed solvent whose main solvent is dimethylformamide, dimethylformamide, 1-methyl-2-pyrrolidinone, and dimethyl sulfoxide is used as an inert solvent.

상기한 본 발명의 제조방법은, 상기 화학식 2로 표시되는 화합물을 출발물질로 사용하여 연속적인 공정을 통하여 일용기 반응(one-pot reaction)으로 목적하는 상기 화학식 1로 표시되는 화합물을 제조할 수 있다.The preparation method of the present invention, using the compound represented by the formula (2) as a starting material can be prepared in the compound represented by the formula (1) as a one-pot reaction through a continuous process (one-pot reaction) have.

한편, 본 발명은 상기한 제조과정을 수행하는 중에 생성되는 신규 중간체 화합물을 본 발명의 권리범위로 포함한다.On the other hand, the present invention includes the novel intermediate compound produced during the above-described manufacturing process as the scope of the present invention.

본 발명이 특징으로 하는 중간체 화합물은, 하기 화학식 3으로 표시되는 화합물이다.The intermediate compound characterized by the present invention is a compound represented by the following general formula (3).

Figure 112005041757564-pat00009
Figure 112005041757564-pat00009

상기 화학식 3에서, R1은 수소원자, 알카리금속원자, 또는 C1~C10의 알킬치환된 실릴 기를 나타내고; A는 P(R4)3I, 또는 P(O)(OR4)2를 나타내고; R4는 C1~C6의 알킬기, 페닐기, 또는 C1~C6의 알콕시 치환된 페닐기를 나타낸다.In Formula 3, R 1 represents a hydrogen atom, an alkali metal atom, or an alkyl substituted silyl group of C 1 to C 10 ; A represents P (R 4 ) 3 I, or P (O) (OR 4 ) 2 ; R 4 represents a C 1 to C 6 alkyl group, a phenyl group, or a C 1 to C 6 alkoxy substituted phenyl group.

상기 화학식 3으로 표시되는 중간체 화합물을 구체적으로 예시하면, 하기 화학식 3a로 표시되는 화합물이 포함될 수 있다.Specific examples of the intermediate compound represented by Formula 3 may include a compound represented by Formula 3a.

Figure 112005041757564-pat00010
Figure 112005041757564-pat00010

상기 화학식 3a에서, R1은 상기 화학식 3에서 정의한 바와 같다.In Formula 3a, R 1 is as defined in Formula 3.

또한, 본 발명이 특징으로 하는 다른 중간체 화합물은 하기 화학식 4로 표시되는 화합물이다.In addition, another intermediate compound characterized by the present invention is a compound represented by the following formula (4).

Figure 112005041757564-pat00011
Figure 112005041757564-pat00011

상기 화학식 4에서, R1은 수소원자, 알카리금속원자, 또는 C1~C10의 알킬치환된 실릴기를 나타내고; B+는 P+(R4)3, 또는 P(O)(OR4)2Y+를 나타내고; R4는 C1~C6의 알킬기, 페닐기, 또는 C1~C6의 알콕시 치환된 페닐기를 나타내고; Y는 알카리금속원자를 나 타낸다.In Formula 4, R 1 represents a hydrogen atom, an alkali metal atom, or an alkyl substituted silyl group of C 1 to C 10 ; B + represents P + (R 4 ) 3 , or P (O) (OR 4 ) 2 Y + ; R 4 represents a C 1 to C 6 alkyl group, a phenyl group, or a C 1 to C 6 alkoxy substituted phenyl group; Y represents an alkali metal atom.

상기 화학식 4로 표시되는 중간체 화합물을 구체적으로 예시하면, 하기 화학식 4a로 표시되는 화합물이 포함될 수 있다.Specific examples of the intermediate compound represented by Formula 4 may include a compound represented by Formula 4a.

Figure 112005041757564-pat00012
Figure 112005041757564-pat00012

상기 화학식 4a에서, R1은 상기 화학식 4에서 정의한 바와 같다.In Formula 4a, R 1 is as defined in Formula 4.

이상에서 설명한 바와 같은 본 발명이 특징으로 하는 상기 화학식 1로 표시되는 글루타릴 7-아미노-3-비닐-세팔로스포란산 유도체는 효소 또는 화학적 공정에 의한 통상의 방법에 의해 글루타릴기를 이탈시켜, 하기 화학식 5로 표시되는 3-알케닐 세펨화합물을 합성할 수 있다.Glutaryl 7-amino-3-vinyl-cephalosporranic acid derivative represented by the formula (1) characterized by the present invention as described above is a glutaryl group by a conventional method by an enzyme or a chemical process By leaving off, a 3-alkenyl cefem compound represented by the following Chemical Formula 5 may be synthesized.

Figure 112005041757564-pat00013
Figure 112005041757564-pat00013

상기 화학식 5로 표시되는 화합물은 세팔로스포린계 항생제를 합성하는 핵심화합물로서, C-7 위치의 아미노기와 C-4 위치의 카르복실기의 종류에 세픽심, 세프디니르, 세프프로질, 세프디토렌등의 다양한 항생제로 합성이 가능하다.Compound represented by the formula (5) is a core compound for synthesizing cephalosporin-based antibiotics, Sepiksim, Cefdinir, Cefprozil, Cefditorene in the kind of amino group and C4 position carboxyl group Synthesis is possible with various antibiotics.

이상에서 설명한 바와 같은 본 발명은 다음의 실시예에 의거하여 더욱 상세 히 설명하겠는 바, 결코 본 발명이 이에 한정되는 것은 아니다.The present invention as described above will be described in more detail based on the following examples, but the present invention is by no means limited thereto.

실시예 1. 7-(4-트리메틸실릴옥시카르보닐-부탄아미도)-3-트리페닐포스포늄메틸-3-세펨-4-카르복실릭-트리메틸실릴에스터-요오드의 합성Example 1.Synthesis of 7- (4-trimethylsilyloxycarbonyl-butaneamido) -3-triphenylphosphoniummethyl-3-cepem-4-carboxylic-trimethylsilylester-iodine

7-(4-트리메틸실릴옥시카르보닐-부탄아미도)-3-요오도메틸-3-세펨-4-카르복실릭-트리메틸실릴에스터 5 g이 든 디클로로메탄 용액에 0 ℃ 하에서 트리페닐 포스핀을 적가하였다. 반응 혼합용액을 10 ℃에서 약 1시간 교반해 준 후 진공에서 용매를 증류시켜 주황색 오일성의 목적화합물을 얻었다. 소량을 취해서 저급알콜 또는 소량의 증류수로 탈실릴화한 후 NMR로 분석하였다.Triphenyl phosphine at 0 ° C. in a dichloromethane solution containing 5 g of 7- (4-trimethylsilyloxycarbonyl-butaneamido) -3-iodomethyl-3-cepem-4-carboxylic-trimethylsilylester Was added drop wise. The reaction mixture was stirred at 10 ° C. for about 1 hour, and then the solvent was distilled off under vacuum to obtain an orange oily target compound. A small amount was taken and desilylated with lower alcohol or a small amount of distilled water and analyzed by NMR.

1H NMR(DMSO-d6, 400MHz) δ(ppm) 1.8-2.0(2H), 2.7(4H), 3.21-3.27(2H), 4.64-4.68(2H), 5.15(1H), 5.89(1H), 6.68(1H), 7.7-7.8(15H) 1 H NMR (DMSO-d 6 , 400 MHz) δ (ppm) 1.8-2.0 (2H), 2.7 (4H), 3.21-3.27 (2H), 4.64-4.68 (2H), 5.15 (1H), 5.89 (1H) , 6.68 (1 H), 7.7-7.8 (15 H)

실시예 2. 7-(4-트리메틸실릴옥시카르보닐-부탄아미도)-3-트리페닐포스포란일리드엔메틸-3-세펨-4-카르복실릭-트리메틸실릴에스터Example 2. 7- (4-Trimethylsilyloxycarbonyl-butaneamido) -3-triphenylphosphoranelidenemethyl-3-cepem-4-carboxylic-trimethylsilyl ester

테트라히드로퓨란 10 mL에 7-(4-트리메틸실릴옥시카르보닐-부탄아미도)-3-트리페닐포스포늄메틸-3-세펨-4-카르복실릭-트리메틸실릴에스터-요오드 11.1 g을 넣고 -10 ℃에서 테트라히드로퓨란 5 mL에 녹아있는 1,1,1,3,3,3-헥사메틸디실라잔 리튬염 2.5 g을 천천히 적가하였다. 반응 중에 암적색의 색깔을 띄어 일리드가 형성됨을 알 수 있다. 이 온도에서 약 30분간 교반하고 용매를 진공에서 증류시켜 7-(4-트리메틸실릴옥시카르보닐-부탄아미도)-3-트리페닐포스포란일리드엔메틸-3-세펨-4-카르복실릭-트리메틸실릴에스터를 얻었다. 11.1 g of 7- (4-trimethylsilyloxycarbonyl-butaneamido) -3-triphenylphosphoniummethyl-3-cepem-4-carboxylic-trimethylsilylester-iodine was added to 10 mL of tetrahydrofuran- 2.5 g of 1,1,1,3,3,3-hexamethyldisilazane lithium salt dissolved in 5 mL of tetrahydrofuran was slowly added dropwise at 10 ° C. It can be seen that the red color is formed during the reaction to the dark red color. Stir at this temperature for about 30 minutes and distill the solvent in vacuo to afford 7- (4-trimethylsilyloxycarbonyl-butaneamido) -3-triphenylphosphoranlidenemethyl-3-cepem-4-carboxylic Trimethylsilyl ester was obtained.

실시예 3. 글루타릴 7-아미노-3-비닐-3-세펨-4-카르복실산Example 3. Glutaryl 7-Amino-3-vinyl-3-cepem-4-carboxylic acid

7-(4-트리메틸실릴옥시카르보닐-부탄아미도)-3-트리페닐포스포늄메틸-3-세펨-4-카르복실릭-트리메틸실릴에스터-요오드 11.1 g을 테트라히드로퓨란 10 mL에 녹인 후 온도를 -10 ℃로 낮추었다. 반응 혼합용액에 N-O-비스트리메틸실릴아세트아미드 12.8 mL를 적가한 후 5분 뒤에 1,1,1,3,3,3-헥사메틸디실라잔 리튬염 2.6 g을 천천히 적가하였다. 반응혼합물이 암적색이 되면, 반응혼합용액의 온도를 -10 ℃로 유지하면서 포말린 가스를 약 5분간 주입하였다. 이 온도에서 1시간 교반 후 0 ℃에서 5시간 교반하였다. 용매를 진공에서 말려준 후 에틸에테르 50 mL와 증류수 20 mL를 넣고 1N 암모니아수로 pH를 8.5로 유지하였다. 30분 후에 물층을 분리하여 에틸에테르 10 mL를 첨가하였다. 1N HCl로 0 ℃에서 pH를 1로 낮추고 1시간 교반 후 유기층을 분리하고 물층은 다시 에틸에테르 10 mL로 추출하였다. 유기용액을 합친 후 진공에서 용매를 증류시켜 글루타릴 7-아미노-3-비닐-3-세펨-4-카르복실산을 얻었다.Dissolve 11.1 g of 7- (4-trimethylsilyloxycarbonyl-butaneamido) -3-triphenylphosphoniummethyl-3-cepem-4-carboxylic-trimethylsilylester-iodine in 10 mL of tetrahydrofuran The temperature was lowered to -10 ° C. 12.8 mL of N-O-bistrimethylsilylacetamide was added dropwise to the reaction mixture, and after 5 minutes, 2.6 g of 1,1,1,3,3,3-hexamethyldisilazane lithium salt was slowly added dropwise. When the reaction mixture became dark red, formalin gas was injected for about 5 minutes while maintaining the temperature of the reaction mixture solution at -10 ° C. After stirring for 1 hour at this temperature, the mixture was stirred for 5 hours at 0 ° C. The solvent was dried in vacuo, and 50 mL of ethyl ether and 20 mL of distilled water were added thereto, and the pH was maintained at 8.5 with 1N ammonia water. After 30 minutes, the water layer was separated and 10 mL of ethyl ether was added. The pH was lowered to 1 at 0 ° C. with 1N HCl, and after stirring for 1 hour, the organic layer was separated and the aqueous layer was extracted with 10 mL of ethyl ether. The organic solutions were combined and the solvent was distilled off in vacuo to yield glutaryl 7-amino-3-vinyl-3-cepem-4-carboxylic acid.

1H NMR(DMSO-d6, 400MHz) δ(ppm) 2.0(2H), 3.0(4H), 3.4(1H), 3.8(1H), 4.6(1H), 5.0(1H), 5.2(1H), 5.5(1H), 6.9(1H), 8.8(1H,NH) 1 H NMR (DMSO-d 6 , 400 MHz) δ (ppm) 2.0 (2H), 3.0 (4H), 3.4 (1H), 3.8 (1H), 4.6 (1H), 5.0 (1H), 5.2 (1H), 5.5 (1H), 6.9 (1H), 8.8 (1H, NH)

실시예 4. 7-아미노-3-비닐-3-세펨-4-카르복실산Example 4. 7-Amino-3-vinyl-3-cepem-4-carboxylic acid

글루타릴 7-아미노-3-비닐-3-세펨-4-카르복실산 5 g을 증류수 20 mL에 넣은 후 1N-수산화나트륨 수용액으로 pH를 8로 맞추었다. 상온에서 효소를 첨가하고 교반하면서 1N-수산화나트륨 수용액으로 pH는 8로 유지시켰다. 2시간 교반 뒤 효소를 여과해서 제거하고 10 mL 아세톤을 첨가 후 0℃ ℃에서 1N-염산으로 pH를 3.5로 낮추었다. 약 3시간 뒤에 생성된 고체를 여과하고 아세톤으로 씻어주어 순수한 7-아미노-3-비닐-3-세펨-4-카르복실산을 얻었다.5 g of glutaryl 7-amino-3-vinyl-3-cepem-4-carboxylic acid was added to 20 mL of distilled water, and the pH was adjusted to 8 with 1N aqueous sodium hydroxide solution. The enzyme was added at room temperature and the pH was maintained at 8 with 1N aqueous sodium hydroxide solution while stirring. After stirring for 2 hours, the enzyme was filtered off, 10 mL acetone was added, and the pH was lowered to 3.5 with 1N hydrochloric acid at 0 ° C. After about 3 hours, the resulting solid was filtered and washed with acetone to obtain pure 7-amino-3-vinyl-3-cepem-4-carboxylic acid.

1H NMR(DMSO-d6, 400MHz) δ(ppm) 3.3(1H), 3.7(1H), 4.7(1H), 4.9(1H), 5.2(1H), 5.5(1H), 6.87(1H) 1 H NMR (DMSO-d 6 , 400 MHz) δ (ppm) 3.3 (1H), 3.7 (1H), 4.7 (1H), 4.9 (1H), 5.2 (1H), 5.5 (1H), 6.87 (1H)

실시예 5. 글루타릴 7-아미노-3-(프로프-1-엔일)-3-세펨-4-카르복실산Example 5 Glutaryl 7-Amino-3- (prop-1-enyl) -3-cepem-4-carboxylic acid

7-(4-트리메틸실릴옥시카르보닐-부탄아미도)-3-트리페닐포스포늄메틸-3-세펨-4-카르복실릭-트리메틸실릴에스터-요오드를 테트라히드로퓨란 10 mL에 녹인 후 온도를 -10 ℃로 낮추었다. 반응 혼합용액에 N-O-비스트리메틸실릴아세트아미드 6.4 mL와 디메틸포름아세트아미드 12 mL를 적가 후 5분 뒤에 1,1,1,3,3,3-헥사메틸디실라잔 리튬염 2.6 g을 천천히 적가하였다. 반응혼합물이 암적색이 되면, 반응혼합용액의 온도를 -10 ℃로 유지하면서 아세트알데히드 1.5 mL를 천천히 적가하고 상기 실시예 3과 같은 방법으로 진행하여 글루타릴 7-아미노-3-(프로프-1-엔일)-3-세펨-4-카르복실산을 얻었다.7- (4-trimethylsilyloxycarbonyl-butaneamido) -3-triphenylphosphoniummethyl-3-cepem-4-carboxylic-trimethylsilylester-iodine is dissolved in 10 mL of tetrahydrofuran and the temperature is decreased. Lowered to -10 ° C. 6.4 mL of NO-bistrimethylsilylacetamide and 12 mL of dimethylformacetamide were added dropwise to the reaction mixture, followed by 5 minutes of slow dropwise addition of 2.6 g of 1,1,1,3,3,3-hexamethyldisilazane lithium salt. It was. When the reaction mixture becomes dark red, 1.5 mL of acetaldehyde is slowly added dropwise while maintaining the temperature of the reaction mixture solution at -10 ° C. and proceeding in the same manner as in Example 3 to glutaryl 7-amino-3- (prop- 1-enyl) -3-cepem-4-carboxylic acid was obtained.

1H NMR(DMSO-d6, 400MHz) δ(ppm) 1.50(3H, Z), 1.7(2H, Z or E),1.8(3H, E), 1.9(2H, Z or E), 2.5(4H, Z or E), 3.0(4H, Z or E), 3.5(2H, Z or E), 4.69-4.75(1H, Z or E), 5.01-5.2(1H, Z or E), 5.6(1H, Z), 6.0-6.7(1H, Z or E), 7.2-7.4(1H, E), 9.0(1H, NH) 1 H NMR (DMSO-d 6 , 400 MHz) δ (ppm) 1.50 (3H, Z), 1.7 (2H, Z or E), 1.8 (3H, E), 1.9 (2H, Z or E), 2.5 (4H , Z or E), 3.0 (4H, Z or E), 3.5 (2H, Z or E), 4.69-4.75 (1H, Z or E), 5.01-5.2 (1H, Z or E), 5.6 (1H, Z), 6.0-6.7 (1H, Z or E), 7.2-7.4 (1H, E), 9.0 (1H, NH)

실시예 6. 7-아미노-3-(프로프-1-엔일)-3-세펨-4-카르복실산Example 6. 7-Amino-3- (prop-1-enyl) -3-cepem-4-carboxylic acid

글루타릴 7-아미노-3-(프로프-1-엔일)-3-세펨-4-카르복실산 5 g을 상기 실시예 4와 같은 방법으로 진행하여 7-아미노-3-(프로프-1-엔일)-3-세펨-4-카르복실산을 얻었다.5 g of glutaryl 7-amino-3- (prop-1-enyl) -3-cepem-4-carboxylic acid were proceeded in the same manner as in Example 4 to obtain 7-amino-3- (prop- 1-enyl) -3-cepem-4-carboxylic acid was obtained.

1H NMR(DMSO-d6, 400MHz) δ(ppm) 1.53(3H, Z), 1.73(3H, E), 3.34-3.36(2H, Z or E), 4.66-4.71(1H, Z or E), 4.89-4.96(1H, Z or E), 5.48-5.57(1H, Z), 5.96-6.56(1H, Z or E), 6.56-6.6(1H, E) 1 H NMR (DMSO-d 6 , 400 MHz) δ (ppm) 1.53 (3H, Z), 1.73 (3H, E), 3.34-3.36 (2H, Z or E), 4.66-4.71 (1H, Z or E) , 4.89-4.96 (1H, Z or E), 5.48-5.57 (1H, Z), 5.96-6.56 (1H, Z or E), 6.56-6.6 (1H, E)

실시예 7. 글루타릴 7-아미노-3-[2-(4-메틸-5-티아졸)비닐]-3-세펨-4-카르복실산Example 7 Glutaryl 7-Amino-3- [2- (4-methyl-5-thiazole) vinyl] -3-cepem-4-carboxylic acid

7-(4-트리메틸실릴옥시카르보닐-부탄아미도)-3-트리페닐포스포늄메틸-3-세펨-4-카르복실릭-트리메틸실릴에스터-요오드 11.1 g을 테트라히드로퓨란 10 mL에 녹인 후 온도를 -10 ℃로 낮추었다. 반응 혼합용액에 N-O-비스트리메틸실릴아세트아미드 6.4 mL와 디메틸포름아세트아미드 12.8 mL를 적가 후 5분 뒤에 1,1,1,3,3,3-헥사메틸디실라잔 리튬염 2.5 g을 천천히 적가하였다. 반응혼합물이 암적색이 되면, 반응혼합용액의 온도를 -10 ℃로 유지하면서 4-메틸-티아졸-5-카브알데히드를 천천히 적가하고 상기 실시예 3과 같은 방법으로 진행하여 글루타릴 7-아미노-3-[2-(4-메틸-5-티아졸)비닐]-3-세펨-4-카르복실산을 얻었다.Dissolve 11.1 g of 7- (4-trimethylsilyloxycarbonyl-butaneamido) -3-triphenylphosphoniummethyl-3-cepem-4-carboxylic-trimethylsilylester-iodine in 10 mL of tetrahydrofuran The temperature was lowered to -10 ° C. 6.4 mL of NO-bistrimethylsilylacetamide and 12.8 mL of dimethylformacetamide were added dropwise to the reaction mixture, and 5 g of 1,1,1,3,3,3-hexamethyldisilazane lithium salt was slowly added dropwise after 5 minutes. It was. When the reaction mixture becomes dark red, 4-methyl-thiazole-5-carbaldehyde is slowly added dropwise while maintaining the temperature of the reaction mixture solution at -10 ° C, and proceeds in the same manner as in Example 3 to glutaryl 7-amino -3- [2- (4-methyl-5-thiazole) vinyl] -3-cepem-4-carboxylic acid was obtained.

1H NMR(DMSO-d6, 400MHz) δ(ppm) 1.7(2H, Z or E), 2.3(4H, Z or E)2.35(3H, Z), 2.44(3H, E), 3.15-3.44(2H, Z), 3.6-4.09(2H, E), 4.77(1H, Z), 4.81(1H, E), 5.02(1H, Z), 5.06(1H, E), 6.3(1H, Z), 6.68(1H, Z), 7.11(2H, E), 8.87(1H, E), 8.90(1H, Z), 9.3(1H, NH) 1 H NMR (DMSO-d 6 , 400 MHz) δ (ppm) 1.7 (2H, Z or E), 2.3 (4H, Z or E) 2.35 (3H, Z), 2.44 (3H, E), 3.15-3.44 ( 2H, Z), 3.6-4.09 (2H, E), 4.77 (1H, Z), 4.81 (1H, E), 5.02 (1H, Z), 5.06 (1H, E), 6.3 (1H, Z), 6.68 (1H, Z), 7.11 (2H, E), 8.87 (1H, E), 8.90 (1H, Z), 9.3 (1H, NH)

실시예 8. 7-아미노-3-[2-(4-메틸-5-티아졸)비닐]-3-세펨-4-카르복실산Example 8. 7-Amino-3- [2- (4-methyl-5-thiazole) vinyl] -3-cepem-4-carboxylic acid

글루타릴 7-아미노-3-[2-(4-메틸-5-티아졸)비닐]-3-세펨-4-카르복실산 5 g을 상기 실시예 4와 같은 방법으로 진행하여 7-아미노-3-[2-(4-메틸-5-티아졸)비닐]-3-세펨-4-카르복실산을 얻었다.5 g of glutaryl 7-amino-3- [2- (4-methyl-5-thiazole) vinyl] -3-cefe-4-carboxylic acid were proceeded in the same manner as in Example 4 to obtain 7 - amino. -3- [2- (4-methyl-5-thiazole) vinyl] -3-cepem-4-carboxylic acid was obtained.

1H NMR(DMSO-d6, 400MHz) δ(ppm) 2.35(3H, Z), 2.44(3H, E), 3.15-3.44(2H, Z), 3.6-4.09(2H, E), 4.77(1H, Z), 4.81(1H, E), 5.02(1H, Z), 5.06(1H, E), 6.3(1H, Z), 6.68(1H, Z), 7.11(2H, E), 8.87(1H, E), 8.90(1H, Z) 1 H NMR (DMSO-d 6 , 400 MHz) δ (ppm) 2.35 (3H, Z), 2.44 (3H, E), 3.15-3.44 (2H, Z), 3.6-4.09 (2H, E), 4.77 (1H , Z), 4.81 (1H, E), 5.02 (1H, Z), 5.06 (1H, E), 6.3 (1H, Z), 6.68 (1H, Z), 7.11 (2H, E), 8.87 (1H, E), 8.90 (1 H, Z)

실시예 9. 글루타릴 7-아미노-3-스티릴-3-세펨-4-카르복실산Example 9 Glutaryl 7-Amino-3-Styryl-3-Cefem-4-carboxylic Acid

7-(4-트리메틸실릴옥시카르보닐-부탄아미도)-3-트리페닐포스포늄메틸-3-세펨-4-카르복실릭-트리메틸실릴에스터-요오드를 테트라히드로퓨란 10 mL에 녹인 후 온도를 -10 ℃로 낮추었다. 반응 혼합용액에 N-O-비스트리메틸실릴아세트아미드 4.8 mL와 디메틸포름아세트아미드 10 mL를 적가 후 5분 뒤에 1,1,1,3,3,3-헥사메틸디실라잔 리튬염 3 g을 천천히 적가하였다. 반응혼합물이 암적색이 되면, 반응혼합용액의 온도를 -10 ℃로 유지하면서 벤즈알데히드 1.98 mL를 천천히 적가하고 상기 실시예 3과 같은 방법으로 진행하여 글루타릴 7-아미노-3-스티릴-3-세펨-4-카르복실산을 얻었다.7- (4-trimethylsilyloxycarbonyl-butaneamido) -3-triphenylphosphoniummethyl-3-cepem-4-carboxylic-trimethylsilylester-iodine is dissolved in 10 mL of tetrahydrofuran and the temperature is decreased. Lowered to -10 ° C. 4.8 mL of NO-bistrimethylsilylacetamide and 10 mL of dimethylformacetamide were added dropwise to the reaction mixture, followed by 5 minutes of 3 g of 1,1,1,3,3,3-hexamethyldisilazane lithium salt. It was. When the reaction mixture becomes dark red, 1.98 mL of benzaldehyde is slowly added dropwise while maintaining the temperature of the reaction mixture solution at -10 ° C. and proceeding in the same manner as in Example 3 to glutaryl 7-amino-3-styryl-3- Cefem-4-carboxylic acid was obtained.

1H NMR(DMSO-d6, 400MHz) δ(ppm) 1.6(2H, Z or E), 2.0(4H, Z or E), 2.4-3.7(3H, Z or E), 3.15-3.44(2H, Z), 5.0(1H, Z or E), 5.48(1H, Z or E), 6.32(1H, Z), 6.57(1H, E), 6.76(1H, Z), 7.1-7.3(5H, Z or E), 7.6(1H, E), 8.89(1H, NH, Z), 8.95(1H, NH, E) 1 H NMR (DMSO-d 6 , 400 MHz) δ (ppm) 1.6 (2H, Z or E), 2.0 (4H, Z or E), 2.4-3.7 (3H, Z or E), 3.15-3.44 (2H, Z), 5.0 (1H, Z or E), 5.48 (1H, Z or E), 6.32 (1H, Z), 6.57 (1H, E), 6.76 (1H, Z), 7.1-7.3 (5H, Z or E), 7.6 (1H, E), 8.89 (1H, NH, Z), 8.95 (1H, NH, E)

실시예 10. 7-아미노-3-스티릴-3-세펨-4-카르복실산Example 10. 7-Amino-3-styryl-3-cepem-4-carboxylic acid

글루타릴 7-아미노-3-스티릴-3-세펨-4-카르복실산 5 g을 상기 실시예 4와 같은 방법으로 진행하여 7-아미노-3-스티릴-3-세펨-4-카르복실산을 얻었다.5 g of glutaryl 7-amino-3-styryl-3-cepem-4-carboxylic acid was proceeded in the same manner as in Example 4 to obtain 7-amino-3-styryl-3-cepem-4-car Acid was obtained.

1H NMR(DMSO-d6, 400MHz) δ(ppm) 2.35(3H, Z), 2.44(3H, E), 3.15-3.44(2H, Z), 3.6-4.09(2H, E), 4.77(1H, Z), 4.81(1H, E), 5.02(1H, Z), 5.06(1H, E), 6.3(1H, Z), 6.68(1H, Z), 7.11(2H, E), 8.87(1H, E), 8.90(1H, Z) 1 H NMR (DMSO-d 6 , 400 MHz) δ (ppm) 2.35 (3H, Z), 2.44 (3H, E), 3.15-3.44 (2H, Z), 3.6-4.09 (2H, E), 4.77 (1H , Z), 4.81 (1H, E), 5.02 (1H, Z), 5.06 (1H, E), 6.3 (1H, Z), 6.68 (1H, Z), 7.11 (2H, E), 8.87 (1H, E), 8.90 (1 H, Z)

실시예 11. 글루타릴 7-아미노세팔로스포란산에서 3-비닐세펨 (연속 반응)Example 11. 3-vinyl cefem (continuous reaction) in glutaryl 7-aminocephalosporanic acid

질소하에서 글루타릴 7-아미노세팔로스포란산 10 g을 디클로메탄 20 mL에 녹인 후 헥사메틸디실라잔 6.6 mL를 첨가하고 환류시켰다. 약 2시간 후 혼탁한 액이 투명해지면 실릴화가 완결된 것으로 판단하였다. 0 ℃ 및 질소 기류 하에서 디클로로메탄에 요오드 트리메틸실란 4.45 mL를 주입 후 트리페닐포스핀 8.2 g을 넣고 1시간 교반하였다. 연노란색의 반응 혼합액을 실릴화시킨 글루타릴 7-아미노세팔로스포란산 용액에 적가하였다. 1시간 상온에서 교반하고 진공에서 디클로메탄 용매가 10 mL 이하가 될 때까지 제거하였다. 반응 혼합용액에 테트라히드로퓨란 10 mL를 첨가한 후 온도를 -10 ℃로 낮추었다. N-O-비스트리메틸실릴아세트아미드 약 6 mL와 디메틸포름아세트아미드 약 10 mL를 적가 후 5분 뒤에 헥사메틸디실라잔 리튬염(1.2~1.5 당량)을 천천히 적가하였다. 암적색의 반응혼합용액을 -10 ℃를 유지하면서 30분간 교반한 후 알데히드를 적가하였다. 이 온도에서 1시간 교반 후 0 ℃로 온도를 올려 5시간 정도 더 교반하였다. 목적화합물에 따라 A와 B방법으로 얻을 수 있다.Under nitrogen, 10 g of glutaryl 7-aminocephalosporranic acid was dissolved in 20 mL of dichloromethane, and then 6.6 mL of hexamethyldisilazane was added and refluxed. After about 2 hours, when the turbid solution became clear, it was judged that the silylation was completed. After injecting 4.45 mL of iodine trimethylsilane into dichloromethane at 0 ° C. and nitrogen stream, 8.2 g of triphenylphosphine was added thereto, followed by stirring for 1 hour. The light yellow reaction mixture was added dropwise to the silylated glutaryl 7-aminocephalosporanic acid solution. The mixture was stirred at room temperature for 1 hour and removed in vacuo until the dichloromethane solvent was less than 10 mL. 10 mL of tetrahydrofuran was added to the reaction mixture, and the temperature was lowered to -10 ° C. About 6 mL of N-O-bistrimethylsilylacetamide and about 10 mL of dimethylformacetamide were added dropwise, and 5 minutes later, hexamethyldisilazane lithium salt (1.2-1.5 equivalents) was slowly added dropwise. The dark red reaction mixture solution was stirred for 30 minutes while maintaining at -10 ° C, and then aldehyde was added dropwise. After stirring at this temperature for 1 hour, the temperature was raised to 0 ° C. and stirred for about 5 hours. Depending on the target compound, it can be obtained by A and B methods.

A. 진공으로 용매를 제거하고, 10% 염산용액 5 mL와 에틸에테르 10 mL를 넣고 1시간 교반 후 분리하고, 수용액은 다시 에틸에테르 10 mL로 씻어주었다. 유기용매에 황산마그네슘를 넣고 여과한 후 용매를 제거하여 글루타릴 7-아미노-3-비닐-세팔로스포란산을 얻었다. A. The solvent was removed in vacuo, 5 mL of 10% hydrochloric acid solution and 10 mL of ethyl ether were added thereto, stirred for 1 hour, separated, and the aqueous solution was washed with 10 mL of ethyl ether again. Magnesium sulfate was added to the organic solvent, and after filtration, the solvent was removed to obtain glutaryl 7-amino-3-vinyl-cephalosporonic acid.

B. 증류수 10 mL를 주입 후 포화탄산나트륨 수용액으로 pH를 8로 맞추었다. 디클로로메탄 20 mL를 더 넣고, 1시간 교반해 준 후 수층을 분리하였다. 수층에 효소 3 g을 넣고 포화탄산나트륨 수용액으로 pH 8로 유지하였다. 1시간 뒤 반응이 종결되면 효소를 여과하여 제거하고, 아세톤 10 mL를 첨가 후 온도를 0 ℃로 낮추었다. 1N 염산 용액을 이용하여 pH를 3.5로 낮추고, 이 온도에서 3시간 교반하여 7-아미노-3-비닐-세팔로스포란산을 얻었다.B. After injecting 10 mL of distilled water, the pH was adjusted to 8 with saturated aqueous sodium carbonate solution. 20 mL of dichloromethane was further added, the mixture was stirred for 1 hour, and the aqueous layer was separated. 3 g of enzyme was added to the aqueous layer and maintained at pH 8 with saturated aqueous sodium carbonate solution. After 1 hour, when the reaction was terminated, the enzyme was filtered off. After addition of 10 mL of acetone, the temperature was lowered to 0 ° C. The pH was lowered to 3.5 using 1N hydrochloric acid solution, and stirred at this temperature for 3 hours to obtain 7-amino-3-vinyl-cephalosporanic acid.

이상에서 설명한 바와 같이, 본 발명에서는 7-아미노세팔로스포린의 전구체에 해당하는 상기 화학식 2로 표시되는 글루타릴 7-아미노세팔로스포란산을 출발물질로 사용하고, 신규 구조의 중간체 화합물의 합성과정을 경유함으로써 기존의 제조방법에서 지적된 단점들을 보완하여 매우 경제적으로 상기 화학식 1로 표시되는 글루타릴 7-아미노-3-비닐-세팔로스포란산 유도체를 제조할 수 있었다.As described above, in the present invention, a glutaryl 7-aminocephalosporranic acid represented by Formula 2 corresponding to a precursor of 7-aminocephalosporin is used as a starting material, By way of synthesis, the glutaryl 7-amino-3-vinyl-cephalosporanic acid derivative represented by Chemical Formula 1 could be prepared very economically by supplementing the disadvantages pointed out in the existing manufacturing method.

특히, 본 발명에서 출발물질로 사용하는 상기 화학식 2로 표시되는 글루타릴 7-아미노세팔로스포란산은 C-7 위치의 아미노기가 글루타릴기에 의해 보호되어 있으므로 7-아미노세팔로스포란산에 비하여 부반응과 미반응 생성이 적고, 화학 합성적으로 보다 용이한 장점이 있다. 즉, 글루타릴 7-아미노세팔로스포란산에 결합된 두 개의 카르복실산은 실릴기로 보호하여 탈보호 단계를 생략함으로써 공정단계를 간소화시켰으며, 반응 시간은 1 내지 2시간 정도 소요되므로 기존의 7-아미노세팔로스포린 사용에 따른 긴 반응시간(over-night)에 비해 훨씬 단축시킨 효과를 얻을 수 있었다. 또한, 글루타릴 7-아미노세팔로스포란산은 7-아미노세팔로스포란산에 비하여 휠씬 저렴해서 산업적 이용에 있어 매우 유리한 장점도 있다.In particular, glutaryl 7-aminocephalosporanic acid represented by the formula (2) used as a starting material in the present invention is because the amino group of the C-7 position is protected by the glutaryl group 7-aminocephalosporanic acid Compared with less side reactions and unreacted generations, there is an advantage in chemical synthesis. That is, the two carboxylic acids bonded to glutaryl 7-aminocephalosporranic acid were protected by a silyl group, thereby simplifying the process step by eliminating the deprotection step, and the reaction time takes about 1 to 2 hours. Compared to the long over-night of using 7-aminocephalosporin, a much shorter effect was obtained. In addition, glutaryl 7-aminocephalosporranic acid is much cheaper than 7-aminocephalosporranic acid, which is also very advantageous for industrial use.

그리고, 본 발명의 제조과정 중에 합성되는 신규 중간체 화합물 및 최종 화합물들은 산 수용액에서 쉽게 유기용매로 추출하여 얻을 수 있어 전체적인 제조 수율이 높은 장점도 있다.In addition, the new intermediate compound and the final compound synthesized during the preparation process of the present invention can be easily extracted with an organic solvent in an aqueous acid solution, there is an advantage that the overall production yield is high.

Claims (16)

하기 화학식 1로 표시되는 것임을 특징으로 하는 글루타릴 7-아미노-3-비닐-세팔로스포란산 유도체 :Glutaryl 7-amino-3-vinyl-cephalosporanic acid derivative, characterized in that represented by the following formula (1): [화학식 1][Formula 1]
Figure 112005043723097-pat00014
Figure 112005043723097-pat00014
 상기 화학식 1에서, R1은 수소원자, 알카리금속원자, 또는 C1~C10의 알킬치환된 실릴기를 나타내고; R2와 R3는 서로 같거나 다른 것으로서 수소원자, C1~C6의 알킬기, 페닐기, 티아졸기, 또는 C1~C6의 알킬 치환된 티아졸기를 나타낸다.In Formula 1, R 1 represents a hydrogen atom, an alkali metal atom, or an alkyl substituted silyl group of C 1 to C 10 ; R 2 and R 3, which may be the same or different, represent a hydrogen atom, an alkyl group of C 1 to C 6 , a phenyl group, a thiazole group, or an alkyl substituted thiazole group of C 1 to C 6 . 제 1 항에 있어서, 상기 R1은 C1~C10의 알킬치환된 실릴기이고; R2와 R3는 서로 같거나 다른 것으로서 수소원자, 메틸기, 에틸기, n-프로필기, 이소부틸기, tert-부틸기, 티아졸기; 또는 4-메틸 티아졸인 것을 특징으로 하는 글루타릴 7-아미노-3-비닐-세팔로스포란산 유도체.The compound of claim 1, wherein R 1 is a C 1 to C 10 alkyl substituted silyl group; R 2 and R 3 are the same as or different from each other and are a hydrogen atom, a methyl group, an ethyl group, an n-propyl group, an isobutyl group, a tert-butyl group, a thiazole group; Or 4-methyl thiazole; glutaryl 7-amino-3-vinyl-cephalosporan acid derivative. 제 1 항에 있어서, 하기 화학식 1a로 표시되는 글루타릴 7-아미노-3-비닐-세팔로스포란산 유도체 :The glutaryl 7-amino-3-vinyl-cephalosporanic acid derivative according to claim 1, which is represented by Formula 1a: [화학식 1a][Formula 1a]
Figure 112005043723097-pat00015
Figure 112005043723097-pat00015
 제 1 항에 있어서, 하기 화학식 1b로 표시되는 글루타릴 7-아미노-3-비닐-세팔로스포란산 유도체 :The glutaryl 7-amino-3-vinyl-cephalosporanic acid derivative according to claim 1, which is represented by Formula 1b: [화학식 1b][Formula 1b]
Figure 112005043723097-pat00016
Figure 112005043723097-pat00016
 제 1 항에 있어서, 하기 화학식 1c로 표시되는 글루타릴 7-아미노-3-비닐-세팔로스포란산 유도체 :The glutaryl 7-amino-3-vinyl-cephalosporanic acid derivative according to claim 1, which is represented by Formula 1c: [화학식 1c][Formula 1c]
Figure 112005043723097-pat00017
Figure 112005043723097-pat00017
 하기 화학식 3으로 표시되는 것을 특징으로 하는 중간체 화합물 :Intermediate compound, characterized in that represented by the formula [화학식 3][Formula 3]
Figure 112005041757564-pat00018
Figure 112005041757564-pat00018
 상기 화학식 3에서, R1은 수소원자, 또는 C1~C10의 알킬치환된 실릴기를 나타내고; A는 P(R4)3I, 또는 P(O)(OR4)2를 나타내고; R4는 C1~C6의 알킬기, 페닐기, 또는 C1~C6의 알콕시 치환된 페닐기를 나타낸다.In Formula 3, R 1 represents a hydrogen atom or an alkyl substituted silyl group of C 1 to C 10 ; A represents P (R 4 ) 3 I, or P (O) (OR 4 ) 2 ; R 4 represents a C 1 to C 6 alkyl group, a phenyl group, or a C 1 to C 6 alkoxy substituted phenyl group. 제 6 항에 있어서, 하기 화학식 3a로 표시되어지는 중간체 화합물 :The intermediate compound of claim 6, represented by the following general formula (3a): [화학식 3a][Formula 3a]
Figure 112005041757564-pat00019
Figure 112005041757564-pat00019
 상기 화학식 3a에서, R1은 상기 청구항 6에서 정의한 바와 같다.In Formula 3a, R 1 is as defined in claim 6 above. 하기 화학식 4로 표시되는 중간체 화합물 :Intermediate compound represented by the following formula (4): [화학식 4][Formula 4]
Figure 112005041757564-pat00020
Figure 112005041757564-pat00020
 상기 화학식 4에서, R1은 수소원자, 또는 C1~C10의 알킬치환된 실릴기를 나타내고; B+는 P+(R4)3, 또는 P(O)(OR4)2Y+를 나타내고; R4는 C1~C6의 알킬기, 페닐기, 또는 C1~C6의 알콕시 치환된 페닐기를 나타내고; Y는 알카리금속원자를 나타낸다.In Formula 4, R 1 represents a hydrogen atom or an alkyl substituted silyl group of C 1 to C 10 ; B + represents P + (R 4 ) 3 , or P (O) (OR 4 ) 2 Y + ; R 4 represents a C 1 to C 6 alkyl group, a phenyl group, or a C 1 to C 6 alkoxy substituted phenyl group; Y represents an alkali metal atom. 제 8 항에 있어서, 하기 화학식 4a로 표시되어지는 중간체 화합물 :The intermediate compound of claim 8, represented by the following general formula (4a): [화학식 4a][Formula 4a]
Figure 112005041757564-pat00021
Figure 112005041757564-pat00021
 상기 화학식 4a에서, R1은 상기 청구항 8에서 정의한 바와 같다.In Formula 4a, R 1 is as defined in claim 8 above. 다음의 제조과정을 포함하여 이루어지는 것을 특징으로 하는 제조방법 :A manufacturing method comprising the following manufacturing process: ⅰ) 하기 화학식 2로 표시되는 화합물을 포스포릴화하여, 하기 화학식 3으로 표시되는 화합물을 제조하는 과정,Iii) preparing a compound represented by the following Chemical Formula 3 by phosphorylating the compound represented by the following Chemical Formula 2,
Figure 112005043723097-pat00022
Figure 112005043723097-pat00022
 상기에서, R1은 수소원자, 알카리금속원자, 또는 C1~C10의 알킬치환된 실릴기를 나타내고; A는 P(R4)3I, 또는 P(O)(OR4)2를 나타내고; R4는 C1~C6의 알킬기, 페닐기, 또는 C1~C6의 알콕시 치환된 페닐기를 나타낸다;In the above, R 1 represents a hydrogen atom, an alkali metal atom, or a C 1 to C 10 alkyl substituted silyl group; A represents P (R 4 ) 3 I, or P (O) (OR 4 ) 2 ; R 4 represents a C 1 to C 6 alkyl group, a phenyl group, or a C 1 to C 6 alkoxy substituted phenyl group; ⅱ) 하기 화학식 3으로 표시되는 화합물을 알카리금속의 염기 존재 하에서 반응시켜, 하기 화학식 4로 표시되는 화합물을 제조하는 과정,Ii) preparing a compound represented by the following Chemical Formula 4 by reacting the compound represented by the following Chemical Formula 3 in the presence of an alkali metal base;
Figure 112005043723097-pat00023
Figure 112005043723097-pat00023
 상기에서, R1은 상기에서 정의한 바와 같고; B+는 P+(R4)3, 또는 P(O)(OR4)2Y+를 나타내고; R4는 C1~C6의 알킬기, 페닐기, 또는 C1~C6의 알콕시 치환된 페닐기를 나타내고; Y는 알카리금속원자를 나타낸다;In the above, R 1 is as defined above; B + represents P + (R 4 ) 3 , or P (O) (OR 4 ) 2 Y + ; R 4 represents a C 1 to C 6 alkyl group, a phenyl group, or a C 1 to C 6 alkoxy substituted phenyl group; Y represents an alkali metal atom; ⅲ) 하기 화학식 4로 표시되는 화합물과 알데히드 화합물을 비티히 반응시켜, 하기 화학식 1로 표시되는 글루타릴 7-아미노-3-비닐-세팔로스포란산 유도체를 제조하는 과정,Iii) a glutaryl 7-amino-3-vinyl-cephalosporanic acid derivative represented by the following Chemical Formula 1, by reacting the compound represented by the following Chemical Formula 4 with an aldehyde compound,
Figure 112005043723097-pat00024
Figure 112005043723097-pat00024
 상기에서, R1 및 B+는 상기에서 정의한 바와 같고; R2와 R3는 서로 같거나 다른 것으로서 수소원자, C1~C6의 알킬기, 페닐기, 티아졸기, 또는 C1~C6의 알킬 치환된 티아졸기를 나타낸다.In the above, R 1 and B + are as defined above; R 2 and R 3, which may be the same or different, represent a hydrogen atom, an alkyl group of C 1 to C 6 , a phenyl group, a thiazole group, or an alkyl substituted thiazole group of C 1 to C 6 . 제 10 항에 있어서, 상기 ⅰ) 포스포릴화 반응에서는 트리페닐 포스핀, 트리-p-메톡시페닐 포스핀, 트리메틸 포스핀, 트리에틸 포스핀, 트리페닐 포스페이트, 및 트리에틸 포스페이트 중에서 선택된 포스포릴화제를 사용하는 것을 특징으로 하는 제조방법.11. The method of claim 10 wherein the iii) phosphorylation reaction in the phosphoryl selected from triphenyl phosphine, tri-p-methoxyphenyl phosphine, trimethyl phosphine, triethyl phosphine, triphenyl phosphate, and triethyl phosphate A manufacturing method characterized by using a topical agent. 제 11 항에 있어서, 상기 ⅰ) 포스포릴화제가 트리페닐 포스핀인 것을 특징으로 하는 제조방법.12. The process according to claim 11, wherein said i) phosphorylating agent is triphenyl phosphine. 제 10 항에 있어서, 상기 ⅱ) 알카리 금속염기는 헥사메틸디실라잔, 이소프로필아민, 히드라드, 또는 부틸기와 결합된 알카리금속염, 및 아세토아세트산, 벤조산, 피발산, 아세트산, 또는 말로산의 알카리금속염 중에서 선택되는 것을 특징으로 하는 제조방법.The alkali metal base according to claim 10, wherein the alkali metal base is an alkali metal salt bonded with hexamethyldisilazane, isopropylamine, hydride, or a butyl group, and an alkali of acetoacetic acid, benzoic acid, pivalic acid, acetic acid, or malo acid. Method of producing a metal salt. 제 13 항에 있어서, 상기 ⅱ) 알카리 금속염기는 헥사메틸디실라잔과 결합된 알카리금속염인 것을 특징으로 하는 제조방법.The method of claim 13, wherein the alkali metal base ii) is an alkali metal salt combined with hexamethyldisilazane. 제 10 항에 있어서, 상기 ⅲ) 알데히드 화합물은 포름알데히드, 아세트알데히드, 클로로아세트알데히드, 이소부틸알데히드, 벤즈알데히드, 4-메틸-티아졸-5-카브알데히드 및 톨릴알데히드 중에서 선택되는 것을 특징으로 하는 제조방법.The method of claim 10, wherein iii) the aldehyde compound is characterized in that selected from formaldehyde, acetaldehyde, chloroacetaldehyde, isobutylaldehyde, benzaldehyde, 4-methyl-thiazole-5-carbaldehyde and tolylaldehyde Way. 제 15 항에 있어서, 상기 ⅲ) 알데히드 화합물은 포름알데히드, 아세트알데히드는, 및 4-메틸-티아졸-5-카브알데히드 중에서 선택되는 것을 특징으로 하는 제조방법.16. The process according to claim 15, wherein the iii) aldehyde compound is selected from formaldehyde, acetaldehyde, and 4-methyl-thiazole-5-carbaldehyde.
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Publication number Priority date Publication date Assignee Title
KR840001378B1 (en) * 1983-03-09 1984-09-21 김승호 Process for preparing gephabsporaic acid derivatives
KR910001007B1 (en) * 1989-01-27 1991-02-19 영진약품공업 주식회사 Penicillanic acid and cephalosporin derivatives
KR920006509A (en) * 1990-09-05 1992-04-27 이센브룩 라피세 Method for Continuous Conversion of Cephalosporin Derivatives to Glutaryl-7-Aminocephalosporan Acid Derivatives
US20030104515A1 (en) 2001-04-19 2003-06-05 Alvaro Sanchez-Ferrer "Process for preparing cephalosporanic acid derivatives using alpha-ketoacid derivatives"
KR20040098915A (en) * 2003-05-16 2004-11-26 종근당바이오 주식회사 7-Glutaryl imide cephalosporanic acid derivatives and process for preparing it

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR840001378B1 (en) * 1983-03-09 1984-09-21 김승호 Process for preparing gephabsporaic acid derivatives
KR910001007B1 (en) * 1989-01-27 1991-02-19 영진약품공업 주식회사 Penicillanic acid and cephalosporin derivatives
KR920006509A (en) * 1990-09-05 1992-04-27 이센브룩 라피세 Method for Continuous Conversion of Cephalosporin Derivatives to Glutaryl-7-Aminocephalosporan Acid Derivatives
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